Treatment resistant schizophrenia: precision genetics or more of the same? [Conference Abstract]

Background: It is not known whether treatment-resistant schizophrenia (TRS) represents a distinct biological sub-type or simply a more severe form of the same condition. Furthermore little is known about the genetic architecture of treatment resistant schizophrenia (TRS). In this study we use large-scale genetic data to answer 3 questions: 1. Are polygenic and CNV burdens higher in TRS than generic schizophrenia (Sz) samples i.e. those not selected for treatment response -suggesting a more severe form of the condition? 2. Do GWAS and CNV analyses identify genetic risk factors specific to TRS? 3. Do genes identified by GWAS and CNV analyses in TRS hit glutamate and dopamine pathways at different rates than in generic Sz? Methods: 9000 samples of those taking clozapine constituted the TRS sample-cases with a clinical diagnosis of TRS, together with 10 000 healthy controls. The TRS GWAS and CNV analysis followed established procedures for calling, QC and analysis. Polygenic overlap, training on PGC2 schizophrenia, was compared between TRS and generic Sz samples as were rates of CNVs. To identify genetic variants specific to TRS we sought to replicate SNPs from the GWAS in a sample of TRS (n=3000) versus non-TRS cases (n=3000). The pathway analyses focused on dopamine and glutamate/NMDA receptor gene sets. Results: There was evidence that TRS is associated with a minimally stronger polygenic signal than generic Sz samples (r2 (TRS)=0.17, r2 (generic Sz)=0.14). After combining all TRS samples we identified eleven genome-wide significant SNPs in GWAS, 4 of which appear were specific to TRS. The genes associated with these SNPs are involved in neural cell adhesion and neurogenesis. Rates of CNVs were broadly equivalent between samples. There were differences in CNVs hitting genes in dopamine and glutamate pathways. CNVs in TRS cases were associated more strongly with glutamate pathways than in generic Sz. In contrast there was evidence for weaker association for CNVs hitting dopamine pathways in TRS compared with generic Sz. Conclusion: Our results highlight specific polymorphisms associated with TRS and thus point toward the involvement of distinct molecular pathways. There is evidence for a somewhat stronger polygenic signal in TRS compared to generic schizophrenia but no evidence that large CNVs occur at a higher rate in TRS. We present genetic data indicating novel gene set findings that implicate weaker dopamine and stronger glutamate signals for CNVs in TRS compared with generic Sz